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|2axl, 10 NMR models ()|
Solution structure of a multifunctional DNA- and protein-binding domain of human Werner syndrome protein
Werner syndrome (WS) is an autosomal recessive disease that results in premature aging. Mutations in the WS gene (WRN) result in a loss of expression of the WRN protein and predispose WS patients to accelerated aging. As a helicase and a nuclease, WRN is unique among the five human RecQ helicase family members and is capable of multiple functions involved in DNA replication, repair, recombination, and telomere maintenance. A 144-residue fragment of WRN was previously determined to be a multifunctional DNA- and protein-binding domain (DPBD) that interacts with structure-specific DNA and a variety of DNA-processing proteins. In addition, DPBD functions as a nucleolar targeting sequence of WRN. The solution structure of the DPBD, the first of a WRN fragment, has been solved by NMR. DPBD consists of a winged helix-like motif and an unstructured C-terminal region of approximately 20 aa. The putative DNA-binding surface of DPBD has been identified by using known structural and biochemical data. Based on the structural data and on the biochemical data, we suggest a surface on the DPBD for interacting with other proteins. In this structural model, a single winged helix domain binds to both DNA and other proteins. Furthermore, we propose that DPBD functions as a regulatory domain to regulate the enzymatic activity of WRN and to direct cellular localization of WRN through protein-protein interaction.
Solution structure of a multifunctional DNA- and protein-binding motif of human Werner syndrome protein., Hu JS, Feng H, Zeng W, Lin GX, Xi XG, Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18379-84. Epub 2005 Dec 9. PMID:16339893
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[WRN_HUMAN] Defects in WRN are a cause of Werner syndrome (WRN) [MIM:277700]. WRN is a rare autosomal recessive progeroid syndrome characterized by the premature onset of multiple age-related disorders, including atherosclerosis, cancer, non-insulin-dependent diabetes mellitus, ocular cataracts and osteoporosis. The major cause of death, at a median age of 47, is myocardial infarction. Currently all known WS mutations produces prematurely terminated proteins. Defects in WRN may be a cause of colorectal cancer (CRC) [MIM:114500].
[WRN_HUMAN] Multifunctional enzyme that has both magnesium and ATP-dependent DNA-helicase activity and 3'->5' exonuclease activity towards double-stranded DNA with a 5'-overhang. Has no nuclease activity towards single-stranded DNA or blunt-ended double-stranded DNA. Binds preferentially to DNA substrates containing alternate secondary structures, such as replication forks and Holliday junctions. May play an important role in the dissociation of joint DNA molecules that can arise as products of homologous recombination, at stalled replication forks or during DNA repair. Alleviates stalling of DNA polymerases at the site of DNA lesions. Important for genomic integrity. Plays a role in the formation of DNA replication focal centers; stably associates with foci elements generating binding sites for RP-A (By similarity).
About this Structure
- Hu JS, Feng H, Zeng W, Lin GX, Xi XG. Solution structure of a multifunctional DNA- and protein-binding motif of human Werner syndrome protein. Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18379-84. Epub 2005 Dec 9. PMID:16339893
- ↑ Huang S, Lee L, Hanson NB, Lenaerts C, Hoehn H, Poot M, Rubin CD, Chen DF, Yang CC, Juch H, Dorn T, Spiegel R, Oral EA, Abid M, Battisti C, Lucci-Cordisco E, Neri G, Steed EH, Kidd A, Isley W, Showalter D, Vittone JL, Konstantinow A, Ring J, Meyer P, Wenger SL, von Herbay A, Wollina U, Schuelke M, Huizenga CR, Leistritz DF, Martin GM, Mian IS, Oshima J. The spectrum of WRN mutations in Werner syndrome patients. Hum Mutat. 2006 Jun;27(6):558-67. PMID:16673358 doi:10.1002/humu.20337
- ↑ Xue Y, Ratcliff GC, Wang H, Davis-Searles PR, Gray MD, Erie DA, Redinbo MR. A minimal exonuclease domain of WRN forms a hexamer on DNA and possesses both 3'- 5' exonuclease and 5'-protruding strand endonuclease activities. Biochemistry. 2002 Mar 5;41(9):2901-12. PMID:11863428
- ↑ Kamath-Loeb AS, Lan L, Nakajima S, Yasui A, Loeb LA. Werner syndrome protein interacts functionally with translesion DNA polymerases. Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10394-9. Epub 2007 Jun 11. PMID:17563354 doi:10.1073/pnas.0702513104
- ↑ Compton SA, Tolun G, Kamath-Loeb AS, Loeb LA, Griffith JD. The Werner syndrome protein binds replication fork and holliday junction DNAs as an oligomer. J Biol Chem. 2008 Sep 5;283(36):24478-83. doi: 10.1074/jbc.M803370200. Epub 2008 , Jul 2. PMID:18596042 doi:10.1074/jbc.M803370200
- ↑ Zecevic A, Menard H, Gurel V, Hagan E, DeCaro R, Zhitkovich A. WRN helicase promotes repair of DNA double-strand breaks caused by aberrant mismatch repair of chromium-DNA adducts. Cell Cycle. 2009 Sep 1;8(17):2769-78. Epub 2009 Sep 2. PMID:19652551
- ↑ Opresko PL, Sowd G, Wang H. The Werner syndrome helicase/exonuclease processes mobile D-loops through branch migration and degradation. PLoS One. 2009;4(3):e4825. doi: 10.1371/journal.pone.0004825. Epub 2009 Mar 13. PMID:19283071 doi:10.1371/journal.pone.0004825